Planning a pregnancy after lung transplantation: Issues and considerations

Abstract

Pregnancy after a lung transplant is relatively uncommon with a small number of cases in the literature. Here, a pre-pregnancy counselling appointment is described of a woman with a previous lung transplant due to cystic fibrosis planning pregnancy. The case highlights the clinical considerations before embarking on pregnancy. Pregnancy in a lung transplant recipient confers risk to the mother and fetus. It is critical to advise women on potential risks of pregnancy on lung transplant function, take the opportunity to undertake immunosuppressant tailoring (to avoid teratogenic complications) in conjunction with their specialist team with confirmation of stable allograft function before embarking on pregnancy. Risk stratification after careful consideration of the full history can help identify select individuals where pregnancy might be successful. Open discussion around the regular monitoring of lung function, screening for maternal-fetal complications and the risks are required.

Introduction

Pregnancy after a lung transplant is relatively uncommon with a small number of case series in the literature to inform practice. This article describes a pre-pregnancy counselling (PPC) appointment of a woman with a previous lung transplant due to cystic fibrosis (CF) and highlights clinical considerations before embarking on pregnancy. Such pregnancies require careful pre-pregnancy planning and close antenatal monitoring.

Case report

A 33-year-old Caucasian woman with a lung transplant wished to discuss the feasibility of pregnancy and was referred to Obstetric Medicine for a PPC appointment. She had CF, and four years prior to the review had undergone bilateral sequential lung transplant for CF-related lung disease. She also had other CF-related complications including pancreatic insufficiency, chronic rhinosinusitis, spinal osteopenia, iron deficiency anaemia and gastroesophageal reflux. Regular medications included immunosuppression with mycophenolate mofetil (MMF), tacrolimus, prednisolone, antibiotics for chronic respiratory bacterial colonisation, vitamins and pancreatic enzyme replacement (Box 1).

Box 1.

Medication history.

• Tacrolimus (Prograf 3mg twice daily)

• MMF 250mg twice daily

• Prednisolone 5mg OM

• Adcal D3

• Amlodipine

• Azithromycin 500mg (3x/week)

• Colomycin 2megaunits twice daily (neb)

• Cotrimoxazole 480mg once daily

• Creon 10,000 units

• Flixonase

• Menadiol 10mg once daily

• Omeprazole 20mg twice daily

• Ranitidine 150mg twice daily

• Vitamins A, D and E

Deeper review into the respiratory history revealed that since transplantation, she had developed an episode of acute rejection managed with pulsed methylprednisolone with no recurrence thereafter. Her lungs were colonised with a resistant Achromobacter species with previous recurrent infections with Pseudomonas sp. She took co-trimoxazole, the standard treatment for preventing Pneumocystis jirovecii pneumonia, an opportunistic infection with a high mortality rate in lung transplant patients and azithromycin which suppresses chronic lung allograft dysfunction (CLAD). Pulmonary function tests had been performed within the last year and were stable. She was keen for pregnancy but wanted to explore possible risks of becoming pregnant herself. She had a partner and extensive family support.

During the appointment, several points were considered; although 4 years had elapsed since her lung transplantation, there was an open discussion around the limited data on the clinical outcomes of women pregnant with a lung transplant. She was made aware that at that time, there was less evidence available for lung transplants in pregnancy when compared to other types of organ transplantation. Discussion from the literature was centred around the increased risks of graft rejection notably in the postnatal period so careful respiratory monitoring would extend to the postnatal period. Regular lung function testing would be required with measurements of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Additionally, considering the reduced life expectancy of lung transplant recipients (with five-year survival rates around 55%), it is important this aspect is discussed sensitively with patients planning a pregnancy, as their children could face the possibility of losing their mother before reaching adulthood.

In this case, it was discussed that if the woman and her usual respiratory team were accepting of the potential risks of pregnancy, then adapting her current immunosuppression regime could be considered at this stage. She was informed about the teratogenic risks of MMF, including congenital malformations and miscarriage^1,2 and a plan was made to transition her to azathioprine under close supervision by her respiratory team. With regards to azathioprine she was advised that there is no strong evidence of increased risk of congenital malformations, preterm delivery or adverse effects on fetal growth. It was emphasised that it would be essential to confirm stability of this new immunosuppressive regime for at least 3–6 months prior to considering conception.

Remaining medications prednisolone (5 mg daily) and tacrolimus (3 mg twice daily) could continue and would be safe for pregnancy. Tacrolimus often need to be increased during pregnancy and levels should be regularly monitored to ensure they remain within the appropriate target range. She was also reassured about the use of prednisolone (given the majority is metabolised by the placenta) but she was made aware of the need for preconceptual HbA1c and an earlier oral glucose tolerance testing in pregnancy and ensuring blood pressure was in target. With long-term steroids use, appropriate sick day rules would need to be followed and depending upon the final dose of steroids in pregnancy, steroids may need to be considered for labour. The other medications were also addressed, and she was advised she could continue azithromycin and co-trimoxazole during pregnancy. Given that co-trimoxazole inhibits folic acid synthesis she was advised to commence higher 5 mg dose of folic acid preconceptionally. ³ She was advised vitamin D and calcium supplementation should continue since her osteopenia would likely worsen both antenatally and postnatally if breastfeeding. She was reassured to continue her vitamin replacement for her pancreatic insufficiency since it was likely these supplements would not lead to supra-physiological levels in pregnancy.

In terms of fetal assessment, she would require the routine dating, anomaly and growth assessment (due to risks of fetal growth restriction) and preterm labour risks was discussed. Finally, given that approximately 1 in 18 Caucasians are carriers of the CF gene, it was recommended that the patient's partner undergo carrier testing for the CF gene mutation (cystic fibrosis transmembrane conductance regulator). If both partners are carriers, there would be a 25% risk of the offspring being affected by the disease.

In the meantime, it was agreed that she would see her regular respiratory team and advised carefully of the contraceptive options to avoid unplanned pregnancy. Although subfertility is common in this population, unplanned pregnancy is frequently seen in this group and contraceptive advice must be offered.^4–6

The consultation culminated in careful consideration of the following points highlighted in Box 2 to identify individuals where pregnancy might be successful. Although this PPC case predated more recent consensus from expert groups, ⁶ similar aspects of the guidance were covered.

Box 2.

Issues to consider in PPC appointment in women with lung transplantation.

• Timing of pregnancy in relation to time from lung transplant

• Consider history of graft rejection and its previous trajectory

• Most recent pulmonary function tests including FEV1

• Optimisation of immunosuppressive regime

• Optimise other related cystic fibrosis related complications and screen for conditions such as in the case CF-related diabetes (also at risk due to long term steroid use)

• Genetic counselling

• Contraception

• Other reproductive options such as adoption, surrogacy

Discussion

This case focuses on a PPC appointment with a lung transplant recipient with CF seeking advice for future pregnancy. This is becoming more relevant since advances in the treatment for end-stage lung disease with lung transplantation have improved life expectancy. Most recent data from the Organ Procurement and Transplantation Network showed that ∼16% of lung transplant recipients are of childbearing age thus this is a relevant topic for consideration. ⁷ It is important to raise that for CF, there has been a sharp decline in lung transplantation due to improved medical treatments in the last few years.

Generally, for women with bilateral lung transplants, it is advised that pregnancy should be avoided for a minimum of 1–2 years after transplant enabling time for lowest immunosuppressive doses to be achieved and transplant stability.^1,4 Many pregnancies in female lung transplant recipients are unplanned^5,8 and education regarding contraception and timely referral for PPC are required. ⁶

In the literature, there remains a paucity of studies assessing pregnancy outcomes in lung transplant recipients compared to other solid organ transplants. Following the early report of a successful pregnancy after lung transplant, ⁹ established transplant registries such as the National Transplantation Pregnancy Registry (NTPR) have provided some valuable information on maternal-fetal outcomes in pregnancies occurring in lung transplant recipients.^9,10 However, to date the evidence base and current recommendations are still based on small case numbers with a paucity of prospective studies. ⁶ Newer studies detailing pregnancies in lung transplant recipients have brought new insights into maternal and fetal concerns in this group of women.^8,11

Maternal health concerns

Lung graft rejection

The key challenges post lung transplantation relate to potential decline in lung graft function since 5-year survival rates are reported as ∼50% and significant improvements have been achieved from improved donor selection and organ preservation as well as improved postoperative complications. However, longevity of the graft and patient outcomes are poorer than outcomes in other solid organ transplantation. In the context of pregnancy there are concerns around acute lung graft rejection, which is more common in lung/heart-lung transplants recipients (36%) compared to other solid organ transplants such as heart (20%), liver (10%) and kidney (9%) transplants.^9,10 NTPR data (n = 21 women with lung transplants, 30 pregnancies) showed early on that acute lung graft rejection occurred in 17% of women during pregnancy.^9,10

More recently, a French study of 39 pregnancies reported on lung graft rejection in transplant recipients and although there were no acute graft rejection cases during the pregnancy this was a key issue in the postpartum period. ⁸ Furthermore, CLAD is a progressive form of long-term rejection driven by cumulative graft injury from alloimmune responses, repeated infections and ischemia-reperfusion injury, and is a major factor limiting long-term survival after lung transplantation ¹² Bry et al. showed in their study that 10 out of the 15 women with CLAD developed this after pregnancy and, 4 women died and 3 women required re-transplantation of the lungs. ⁸ In a recent meta-analysis of 12 studies (n = 385), graft rejection during pregnancy was reported in 9.8% of lung transplant recipients. ¹¹

Respiratory lung function and respiratory infection risk

There are several physiological changes in lung function during pregnancy. Normally, tidal volume (PT) and minute ventilation (MV) increase but respiratory rate remains unchanged and functional residual capacity (FRC) decreases by approximately 20%. ¹ FEV1 and FVC remain unchanged typically in recipients with lung transplants, and any decline in these parameters may indicate infection or rejection.^5,9,13 Respiratory infections are an important consideration in pregnancy and in a study of 30 pregnant women with lung transplants, 23.3% had symptomatic infections during pregnancy including Pneumocystis jirovecii, Aspergillus pneumonia and respiratory syncytial virus. ⁹ Similar findings were reported in a smaller study in the postpartum phase. ⁵ Opportunistic infections in this cohort have potential for severe consequences in pregnancy. Lung transplant recipients are highly immunosuppressed, which increases susceptibility to such CMV infection which causes pneumonitis, graft dysfunction and systemic disease, threatening the transplant itself but there are also key fetal risks from congenital CMV including as hearing loss, birth defects which pose major concern. Fungal infections are common in lung transplant recipients, and occurrence in pregnancy poses a dilemma given that typical antifungal drugs, such as voriconazole, are not recommended during pregnancy.

Obstetric and neonatal outcomes

Early data from the NTPR on pregnancy in lung transplant recipients revealed from 30 pregnancies, 11 were born preterm (average 33.9 weeks) with mean birthweight of 2206 g with two neonatal deaths reported ⁹ and subsequent 7-year follow-up of the children, revealed no subsequent issues in the children. From the most recent meta-analysis of 385 pregnancies in lung transplant recipients, the most significant obstetric complications reported were related to development of hypertensive disorders of pregnancy, pre-eclampsia and high rates of caesarean delivery. ¹¹ Across these 12 studies 70.% of pregnancies resulted in live birth, stillbirth rate 1.7%, and neonatal deaths reported in 3.9% of pregnancies. ¹¹ Insufficient data were available to comment on preterm birth and congenital anomalies although prematurity and low birthweight babies have been reported. ⁸

Conclusions

Pregnancy in lung transplant confers risk to the mother and fetus. It is critical to advise women on potential risks of pregnancy with a lung transplant, take the opportunity to undertake immunosuppressant tailoring (to avoid teratogenic complications) in conjunction with their specialist team with confirmation of stable allograft function before embarking on pregnancy. Risk stratification after careful consideration of the full history can help identify select individuals where pregnancy might be successful. Open discussion around the regular monitoring of lung function, screening for maternal-fetal complications and the risks are required.